Population Pharmacokinetics of Doripenem in Pediatric Patients and Monte-Carlo Pharmacokinetic-Pharmacodynamic Simulations for Dosing Regimen Assessment

ABSTRACT Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population. This was a prospective, multicenter, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPK analysis was conducted using NONMEM software. The pharmacokinetic data from 95 pediatric patients (age range, 2.1 to 11.7 years) were available for analysis. The PPK was best fitted by a two-compartment model with linear elimination. Covariate analysis verified that body weight and alanine aminotransferase (ALT) had significant effects on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT of >40. Monte Carlo simulation showed that for children with normal liver function, a loading-dose strategy (a loading dose of 15 mg/kg of body weight followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 h (fAUC) to MIC90 (fAUC/MIC) target of 3 h in 53.2% of hypothetical patients, using a normative MIC susceptibility breakpoint of 2 mg/liter. For children with ALT of >40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%. In conclusion, the PPK of azithromycin was evaluated in children with CAP and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation.

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Population pharmacokinetics and dosing optimization of vancomycin in infants, children and adolescents with augmented renal clearance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00897-21 ◽

2021 ◽

Author(s):

Cui-Yao He ◽

Pan-Pan Ye ◽

Bin Liu ◽

Lin Song ◽

John van den Anker ◽

...

Keyword(s):

Body Weight ◽

Population Pharmacokinetics ◽

Renal Clearance ◽

Pharmacokinetic Model ◽

Pediatric Patients ◽

Pediatric Population ◽

Dosing Regimen ◽

Augmented Renal Clearance ◽

Vancomycin Dose ◽

First Order

Augmented renal clearance (ARC) can cause underexposure to vancomycin, thereby increasing the risk of treatment failure. Our objective was to evaluate population pharmacokinetics and optimize the dosing regimen of vancomycin in the pediatric population with ARC. Sparse pharmacokinetic sampling and therapeutic drug monitoring (TDM) data were collected from pediatric patients with ARC treated with vancomycin. A pharmacokinetic model was developed using NONMEM 7.2. The dosing regimen was optimized using Monte Carlo dose simulations. A total of 242 vancomycin serum concentrations from 113 patients (age range 0.4 to 14.9 years, 49 females and 64 males) were available. Mean vancomycin dose was 58.8 mg/kg/day (13.6 mg/kg/dose), and mean vancomycin serum trough concentration was 6.5 mg/L. A one-compartment pharmacokinetic model with first order elimination was developed. Body weight and age were the most significant and positive covariates for clearance and volume of distribution. To the pediatric population with ARC, the current recommended vancomycin dose of 60 mg/kg/day was associated with a high risk of underdosing. To reach the target AUC/MIC of 400-700 in these pediatric patients, the vancomycin dose should be increased to 75 mg/kg/day for infants and children between 1 month and 12 years of age, and 70 mg/kg/day for adolescents between 12 and 18 years of age. In conclusion, a one-compartment pharmacokinetic model with first-order elimination was established with body weight and age as significant covariates. An optimal dosing regimen was developed in pediatric patients with ARC aged 1 month -18 years.

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Optimizing hydroxychloroquine dosing regimen for treatment of pediatric patients with coronavirus disease 2019 using Monte Carlo simulation

Pharmaceutical Sciences Asia ◽

10.29090/psa.2022.01.21.116 ◽

2022 ◽

Vol 49 (1) ◽

pp. 22-33

Author(s):

Lalitphat Treerattanapun ◽

Suwida Tangtrakultham ◽

Nattapong Tidwong ◽

Preecha Montakantikul

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Pediatric Patients ◽

Dosing Regimen

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Population pharmacokinetics and exposure–response of selumetinib and its N‐desmethyl metabolite in pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-021-04274-6 ◽

2021 ◽

Author(s):

Stein Schalkwijk ◽

Li Zhou ◽

Sarit Cohen‐Rabbie ◽

Lokesh Jain ◽

Tomoko Freshwater ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Neurofibromatosis Type 1 ◽

Pediatric Patients ◽

Neurofibromatosis Type ◽

Plexiform Neurofibromas ◽

Exposure Response

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Population Pharmacokinetics of Tobramycin Inhalation Solution in Pediatric Patients With Cystic Fibrosis

Journal of Pharmaceutical Sciences ◽

10.1016/j.xphs.2017.06.010 ◽

2017 ◽

Vol 106 (11) ◽

pp. 3402-3409 ◽

Cited By ~ 4

Author(s):

Xinting Wang ◽

Stephan Koehne-Voss ◽

SivaNaga S. Anumolu ◽

Jing Yu

Keyword(s):

Cystic Fibrosis ◽

Population Pharmacokinetics ◽

Pediatric Patients

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POPULATION PHARMACOKINETICS AND DOSING OPTIMIZATION OF TEICOPLANIN IN CHILDREN WITH MALIGNANT HAEMATOLOGICAL DISEASE

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-310148.46 ◽

2015 ◽

Vol 101 (1) ◽

pp. e1.41-e1

Author(s):

Wei Zhao ◽

Daolun Zhang ◽

Thomas Storme ◽

André Baruchel ◽

Xavier Declèves ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Haematological Malignancy ◽

External Validation ◽

Predictive Performance ◽

Paediatric Population ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

High Risk Population ◽

Dosing Regimen

BackgroundChildren with haematological malignancy represent an identified subgroup of the paediatric population with specific pharmacokinetic parameters. In these patients, inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality, making optimization of the dosing regimen essential. As paediatric data are limited, our aim was to evaluate the population pharmacokinetics of teicoplanin in order to define the appropriate dosing regimen in this high-risk population.MethodsThe current dose of teicoplanin was evaluated in children with haematological malignancy. Population pharmacokinetics of teicoplanin was analysed using NONMEM software. The dosing regimen was optimised based on the final model.ResultsEighty-five children (age range: 0.5 to 16.9 years) were included. Therapeutic drug monitoring and opportunistic samples (n=143) were available for analysis. With the current recommended dose of 10 mg/kg/day, 41 children (48%) had sub-therapeutic steady-state trough concentrations (Css,min<10 mg/liter). A two-compartment pharmacokinetic model with first-order elimination was developed. Systematic covariate analysis identified that bodyweight (size) and creatinine clearance significantly influenced teicoplanin clearance. The model was validated internally. Its predictive performance was further confirmed in an external validation. In order to reach the target AUC of 750 mg·h/L, 18 mg/kg was required for infants, 14 mg/kg for children and 12 mg/kg for adolescents. A patient-tailored dose regimen was further developed and reduced variability in AUC and Css,min values compared to the mg/kg-basis dose, making the modelling approach an important tool for dosing individualization.ConclusionsThis first population pharmacokinetic study of teicoplanin in children with haematological malignancy provided evidence-based support to individualize teicoplanin therapy in this vulnerable population.

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